The links between nutritional status and immune system function become apparent when one examines the diametrically opposite epidemics of malnutrition and overnutrition. Undernourished individuals tend to be immunosuppressed and more susceptible to infections, whereas obese and overweight individuals have higher susceptibility to inflammatory diseases. The dangers of overnutrition have become apparent in the United States where, according the Centers for Disease Control, nearly 33% of adults can be classified as obese or overweight and the incidence of type 2 diabetes mellitus (T2DM) is rapidly rising. Many obesity related comorbidities, including T2DM, appear to be associated with chronic inflammatory processes. The mechanistic relationship between obesity and inflammation involves a complex network of cells and signaling molecules from both the immune system and metabolic system. The long-term goals of this project are to examine the function of natural killer T (NKT) cells, a T lymphocyte subset which recognizes glycolipid antigens, in the development of obesity and its comorbidities. We first aim to investigate the mechanism by which NKT cell activity is modulated by free fatty acids by using an in vitro model of indirect NKT cell activation and a panel of saturated and unsaturated fatty acids. Our second aim will investigate how NKT cell activity is influenced by specific diets. To achieve this goal, we will feed mice a lard diet, a fish oil diet or a low-fat diet, and will analyze NKT cells using flow cytometry, ELISA and ex vivo stimulation assays. Additionally, we will study NKT cell function in mice directly infused with saturated and unsaturated fatty acids. The experiments described in our third aim will investigate the role of NKT cells in the development of diet-induced obesity and insulin resistance. In this aim, we will feed selected diets to mice deficient in NKT cells and will investigate their immunological and metabolic phenotype. Specifically, we will measure weight gain, body composition, insulin resistance, and expression of pro-inflammatory genes in adipose tissue. Obesity is a preeminent public health concern of the 21st century, and inflammation appears to play a central role in the development of both obesity and its comorbidities. NKT cells play key roles in a variety of immune and inflammatory diseases and we aim to study the function of these cells in the pathogenesis of obesity and diabetes. These studies are of great importance to the fields of obesity and diabetes, and could lead to the development of NKT cell-based therapies for these diseases.